Asunto(s)
Técnicas de Diagnóstico Molecular/métodos , Pruebas de Farmacogenómica/métodos , Medicina de Precisión/métodos , Biomarcadores , Sistemas de Apoyo a Decisiones Clínicas , Unión Europea , Humanos , Medicina Molecular/métodos , Terapia Molecular Dirigida , Proteínas de Neoplasias/análisis , Seguridad del Paciente , Receptor ErbB-2/análisis , Trastuzumab/uso terapéutico , Estados UnidosRESUMEN
BACKGROUND: Most human cancer cells have structural aberrations of chromosomal regions leading to loss or gain of gene specific alleles. This study aimed to assess the range of gene copies per nucleus of thymidylate synthase (TYMS), thymidine phosphorylase (TP) and dihydrofolate reductase (DHFR) in colorectal cancer, and to evaluate its prognostic significance following adjuvant chemotherapy, since these enzymes are closely related to efficacy of 5-fluorouracil (5FU). PATIENTS AND METHODS: Consecutive patients (n = 314), who were completely resected for colorectal cancer stages II-IV and adjuvantly treated with 5-FU were retrospectively evaluated. Paraffin embedded tumor specimens were assessed for gene copies per nucleus of TYMS, TP and DHFR by fluorescence in situ hybridisation (FISH) using specific peptide nucleic acid probes. Outcome according to gene copies per nucleus above and below the median were compared. Also TYMS expression, assessed by immunohistochemistry, was associated with TYMS copies per nucleus. RESULTS: The number of gene copies per nucleus were 1.7 (0.7-2.8), 1.8 (0.9-3.1) and 1.8 (1.1-2.7) median (range) for TYMS, TP and DHFR, respectively. TYMS expression was directly associated with TYMS genes per nucleus (p = 0.05). Cox multivariate analysis, adjusted for the prognostic impact of disease stage, vascular tumor invasion, and bowel obstruction at resection, revealed that high TYMS gene copy number was associated with significantly higher risk of recurrence (HR = 1.6; 95%CI 1.1-2.2; p = 0.02) and death (HR = 1.6; 95%CI 1.1-2.3; p = 0.01). No significant differences in outcome appeared according to TP and DHFR gene ratios. CONCLUSION: Aberration of TYMS gene is of significance to expression of TYMS, which may influence the biology and 5-FU sensitivity of colorectal cancer. This may be utilized in the allocation of patients for treatment approaches and for decision on follow-up programs.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Tetrahidrofolato Deshidrogenasa/genética , Timidina Fosforilasa/genética , Timidilato Sintasa/genética , Adulto , Anciano , Análisis de Varianza , Antimetabolitos Antineoplásicos , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Fluorouracilo/uso terapéutico , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Tetrahidrofolato Deshidrogenasa/análisis , Timidina Fosforilasa/análisis , Timidilato Sintasa/análisisRESUMEN
BACKGROUND: Previous analyses of TOP2A and HER2 in the Danish Breast Cancer Coopererative Group (DBCG) trial 89D suggested that TOP2A amplifications and possible also deletions are predictive markers for the effect of adjuvant epirubicin in patients with primary breast cancer. We present an updated and extended statistical analysis, requested for IVD-labeling of TOP2A testing. MATERIAL AND METHODS: In the DBCG trial 89D 980 Danish patients were randomly assigned to nine cycles of intravenous CMF (cyclophosphamide, methotrexate, and fluorouracil) or CEF (cyclophosphamide, epirubicin, and fluorouracil). Archival tumor tissue was collected retrospectively from 806 of these patients in a prospectively designed, biological sub-study, and was successfully analyzed for TOP2A aberrations and HER2 status in 773 samples (96%). Recurrence-free survival (RFS) was the primary endpoint. RESULTS: TOP2A aberrations (amplifications and deletions) were significantly associated with shorter RFS (p<0.0001) and overall survival (OS) (p<0.0001). Deleted cases had worse prognosis than amplified cases. In a Cox proportional hazard model TOP2A was an independent prognostic marker for RFS and OS. Patients with amplifications had a 61% reduction in the risk of an event (p=0.002) and a 51% reduction in the risk of death (p=0.01) if allocated to CEF compared to 6% and 10% in TOP2A normal patients. A similar but non-significant trend (p=0.08) was shown in patients with TOP2A deletions. Clear statistical evidence of a differential benefit, favoring CEF among patients with TOP2A aberrations was found for RFS (p=0.02 for interaction) but not for OS (p=0.14 for interaction). CONCLUSION: In conclusion, this updated analysis of TOP2A aberrations in DBCG trial 89D suggests a differential benefit of adjuvant chemotherapy in patients with primary breast cancer, favoring treatment with epirubicin in patients with TOP2A amplifications, and perhaps deletions. Additional studies are needed to clarify the exact importance of TOP2A deletions on outcome, but deletions have proven to be associated with a very poor prognosis.